The intracellular information transmitters cAMP and cGMP play a role in regulating cell functions. Cyclic nucleotide phosphodiesterases are enzymes which decompose the substances cAMP and cGMP. The cyclic nucleotide phosphodiesterases are often abbreviated as "phosphodiesterases". They are classified into several isozymes. The molecular structure, the regulating functions, the distributions in tissues and in cells, and the specificity of each of those isozymes have been in a stage of clarification. At the same time, there have been brisk investigations for inhibitors which are specific to the isozymes of the phosphodiesterases and some inhibitors which are useful as pharmaceuticals, etc. have been found.
Phosphodiesterase type IV isozyme (hereinafter, referred to as PDEIV) is one of the isozymes of the phosphodiesterases. PDEIV is distributed in tissues and cells such as brain, kidney, spermary, inflammatory cells, etc. It has a low Km value to cAMP and is an enzyme which specifically decomposes cAMP. When the PDEIV is inhibited, the concentration of cAMP in tissues increases. Therefore, it has been known that inhibitors for PDEIV exhibit various pharmacological actions. For example, PDEIV inhibitors may exhibit action upon the central nervous system such as antidepressant, tranquillizing and antidemential actions. They may also possess antiinflammatory action due to inhibition of isolation of chemical mediators and also to inhibition of perfusion of neutrophils, a bronchodilating action, a relaxing action upon smooth muscles, a protective action upon livers, a diuretic action, etc.
Some isoquinoline derivatives have been known to exhibit pharmaceutical actions such as a peripheral dilating action and an antispasmodic action. For example, drotaverine and the like have been used as pharmaceuticals.
The present inventors have carried out an extensive study on the pharmacological actions of isoquinoline derivatives and found that the isoquinoline derivatives of the present invention have an excellent inhibiting activity with a high specificity to PDEIV.